Primary wild type and COX-2-/- keraticytes were transfected with a retrovirus containing v-H-ras and the transfected keratinocytes grafted on to the back of athymic nude mice. Tumor growth from transfected COX-2 -/- keratinocytes was markedly reduced compared to transfected WT keratinocytes. Tumor incidence was also reduced in mice grafted with the COX-2 -/- keratinocytes. The number of blood vessels per square cm of tumor did not differ with keratinocyte genotype. We did observe lower proliferation rates and higher levels of terminal differentiation in the COX-2 -/- keratinocytes compared to WT keratinocytes as indicated by lowed BRDU incorporation and increased keratin 1 expression, respectively. The levels of apoptosis were similar in WT and COX-2-/- tumors, indicating that increased apoptosis was not a factor in reducing COX-2-/- tumor size.The lower levels of cell replication and increased terminal differentiation were likely the causes of COX-2-/- keratinocytes giving rise to fewer and smaller tumors in this grafting model. In addition, p-EGFR and p-ERK1/2 levels were lower in COX-2-/- keratinocytes/tumors compared to wild type keratinocytes/tumors.